Disubstituted piperazines useful as schistosomiasis agents



United States Patent Office 3,270,004 Patented August 30, 1966 3,270,004 DISUBSTITUTED PIPERAZINES USEFUL AS SCHISTOSOMIASIS AGENTS Arthur Alter, Waukegan, Ill., assignor to Abbott Laboratories, North Chicago, Ill., a corporation of Illinois No Drawing. Filed Dec. 26, 1962, Ser. No. 247,352 17 Claims. (Cl. 260--239) This is a continuation-in-part of application Serial No. 175,336, filed February 23, 1962, now abandoned.

This invention is concerned with novel compounds of the formula as well as their non-toxic, acid-addition salts and a method for their preparation. In this and succeeding formulas, each X is halogen (preferably chlorine or bromine) or loweralkyl; T is piperazine, methylpiperazine, homopiperazine or methylhomopiperazine; Z is a straight or branched alkylene or alkenylene radical containing from 1 to 12 carbon atoms; A is oxygen or sulfur and Y is naphthyl, halonaphthyl or a radical of the formula wherein each R is hydrogen, halogen, nitro, amino, loweralkylamino, diloweralkylamino, straight or branched alkyl containing 1 to 12 carbon atoms, loweralkoxy, alkenyl containing from 2 to 12 carbon atoms or aralkyl such as cyclohexyl and benzyl. The terms loweralkyl or loweralkoxy mean those alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, inclusive, either straight or branched.

These new compounds are active schistosomiasis agents. In a representative operation, mice infested with S. mo'nsoni were orally administered from 100 to 300 mg. per kg. of N (3-chloro-4-methylphenyl)-N'-(4'-t-amylphenoxyhexarnethylene)-piperazine daily for five days which resulted in substantially complete kill of the Worms causing the infection. Preferred compounds of this invention have the formula gfi N N(OH1)1r-O-a1k X wherein n is 2 to 12 and alk is a straight or branched alkyl radical containing from 1 to 12 carbon atoms. More particularly, the preferred compounds can be illustrated by the formula wherein n and alk are as previously defined.

The compounds of the invention can be prepared by refluxing equimolar amounts of a compound of the formula with a compound of the formula hal-Z-AY wherein hal is chlorine or bromine in an inert solvent such as benzene or toluene and in the presence or absence of a hydrohalide acceptor such as triethylamine or pyridine. When the reaction is complete, the reaction mixture is filtered, the filtrate concentrated, the residue dissolved in ether and further treated with alcoholic hydrogen chloride to precipitate the product as a crystalline solid in the form of its hydrochloride. If desired, the free base contained in the filtrate can be reacted with ethereal hydrogen bromide or other acids to form the corresponding hydrobromide, hydroiodine, sulfate, phosphate, acetate, benzoate, salicylate, glycolate, succinate, nicotinate, ascorbate, tartrate, maleate or lactate.

The substituted piperazines and homopiperazines employed as one of the reactants in the present invention are known or can be prepared by methods known per so. A typical method is illustrated in Step A of Example 1. In like manner, the reaction of 3,4-dimethylaniline and diethanolamine will provide l-(3,4-di1methylphenyl)-piperazine which boils at C. at 0.6 mm. pressure. Similarly, the reaction of 3-bromo-4-methylaniline and diethanolamine results in the formation of 1-(3-bromo-4-metl1- ylphenyl)-piperazine having a boiling point of 147 C. at 1.4 mm. pressure and a refractive index 71 of 1.6082. Likewise, the reaction of 3-chloro-4-methylaniline with a compound of the formula Example 1 Step A.Preparation of 1-(3-chloro-4-methylphenyl)- piperazine.

To an ice-cooled mixture of 47.3 g. (0.45 mole) of diethanolamine and 56.6 g. (0.4 mole) of 3- h1 4 amino toluene was added slowly with stirring 100 ml. of hydrobromic acid. The mixture was then heated at 200 C. for 8 hours during which time the water formed was continuously removed by distillation. The solid mass which resulted was dissolved in water and made alkaline with 40% aqueous sodium hydroxide. The aqueous mixture was treated with benzene, the benzene layer dried and fractionally distilled at reduced pressure to obtain the desired 1- 3-chloro-4-methylpheny-l)-piperazine which boiled at l50-156 C. at 2 mm. pressure and had a refractive index n of 1.5900.

Step B.-Preparation of para-t-amylphenoxyhexamethylene bromide.

To a refluxing mixture of 262.4 g. (1.6 moles) of parat-arnylphenol and 488 g. (2.0 moles) of hexarrrethylenedibromide was added slowly with stirring 64 g. (16 moles) of sodium hydroxide dissolved in one liter of water. When the reaction was complete, the low boiling fractions were removed by distillation and the residue fractionally distilled to obtained the desired bromide product which boiled at 189- 194 C. at 2 mm. pressure and had a refractive index 11 of 1.5174.

Step C.--Preparation of N-(3-chloro-4-methyl-phenyl)- N- (4'-t-amylphenoxyhexamethylene) -piperazine.

A mixture of 10.6 g. (0.05 mole) of the compound prepared in Step A, 16.4 g. (0.05 mole) of the compound prepared in Step B, 10.1 g. (0.10 mole) of triethylamine and 125 ml. of toluene was refluxed overnight. The reaction mixture was then filtered and the filtrate concentrated. The residue was dissolved in ether and treated with alcoholic hydrogen chloride to precipitate the desired product as the hydrogen chloride salt which upon recrystallization from benzene melted at 165 C.

Examples 2-19 In the same manner as that described in Example 1, the refluxing of equimolar quantities of 1-(3-chloro-4- methylpheny-l)-piperazine and the appropriate bromide or chloride listed in Table I will produce piperazine compounds of the formula N-Z-Oalk wherein Z and alk are as indicated below.

1 Means dihydrochloride.

6 Examples 20-30 In like manner, the reaction of 1-(3-chloro-4-methylphenyl)-piperazine with the proper bromide or chloride listed in Table I will form compounds of the formula wherein Z and R are as shown below:

M.P. in C. Z R1 of HCl Salt of Piperazine Obtained -(CH2)3 26s ((CH2)4. -butoxy 138 2)-l"---- *Q-(tyclohexyl 1 7 oH.)i- --o1 139 I benzyl CH3 OH2)5 "CH2CH=CH2 161 (CHZ)II 157 '(CH2)6 160 cyclohexyl acme {3 G tnonyl -(CH2)s -t-n0nyl 1 (3H3 (CH2)6 Q I 169 1 Means dihydrochloride.

Examples 31 -33 By replacing 1-(3-chl0ro-4-methylphenyl)-piperazine with 1-(3-bromo-4-methylphenyl)-piperazine or 1-(3,4-dimethylpheny-l)-piperazine in the preceding examples, the corresponding substituted piperazine compounds are obtained which can be readily converted to any acid-addition salt desired. Thus, the following compounds are prepared.

.P. in C. of HClsalt Br H3CN/ N-(GIhh-O-Q-t-amyl 17a l3r zoo-Q-N N(CHz)e-O@t-amyl 164 CH3 HaCN N 2)dy 174 Example 34 F The reaction of 1-(3-chloro-4-methylphenyl)-homo- 20 piperazine, 1-(3-bromo-4-methylphenyl)homopiperazine, a l-(dihalophenyl)-methylpiperazine, a 1-(dihalophenyl)- methylhomopiperazine, a diloweralkylphenylpiperazine or a dihalophenylpiperazine with any of the bromides or chlorides shown in Table 1 will produce the corresponding I O1 substituted derivatives illustrative of which is l having a melting point of 208 C. 0 (31115 Example 35 t-butyl-Q-N N-(om)1-som 5-oH=o1-1 Reacting a piperazine compound of the formula 35 X B1 CH3 0 CIIn TH is p py-N N(CHz)nO- -NH2 Q U X with a halide of the formula hal-Z-S-Y wherein ha] is chlorine or bromine will result in the formation of the cornbutyk =NH CH3 responding derivatives of the general formula F IIQH;

FCW WO, I

CH1 CH3 0'1 CH3 OICH;

TZSY J i X F N N(CHz)o-S -bon1.yl

Illustrative of this type of compound is melting at 146 C.

Other compounds considered to be Within the scope I clalm: of the present invention can be represented as follows: A compound Selected from the p conslstmg of a compound of the formula OH: I r- X N KNOH:CHSNO:

l 01 CH: and non-toxic, acid-addition salts thereof wherein X is lower alkyl, T is selected from the group consisting of CzHi f piperazine, methylpiperazine, homopiperazine and methylhomopiperazine, Z is selected from the group consisting N of straight and branched alkenylene of from 1 to 12 carbon atoms and alkenylene radicals of from 2 to 12 carbon atoms, A is selected from the group consisting of oxygen and sulfur, and Y is selected from the group consisting of naphthyl, halonaphthyl and wherein each R is independently selected from the group consisting of hydrogen, halogen, nitr-o, amino, loweralkylamino, dilowenalkylamino, alkyl of from 1 to 12 carbon atoms, loweralkoxy, alkenyl of from 2 to 12 carbon atoms, cyclohexyl and benzyl.

2. A compound of the formula wherein BA is branched alkylene containing from 2 to 12 carbon atoms.

3. A compound of the formula wherein n is a whole number from 1 to 12 inclusive and alkyl contains from 1 to 12 carbon atoms.

4. A compound of the formula wherein n is a whole number from 1 to 12 inclusive and alkyl contains from 1 to 12 carbon atoms.

5. A compound of the formula wherein n is a whole number from 1 to 12 inclusive and alkyl contains from 1 to 12 carbon atoms.

6. A compound of the formula wherein n is a whole number from 1 to 12 inclusive and wherein n is a whole number from 1 to 12 inclusive and aralkyl is benzyl.

9. A compound of the formula halogen wherein n is a whole number from 1 to 12 inclusive and alkyl contains from 1 to 12 carbon atoms.

halogen- 10. A compound of the formula ICI 11. A compound of the formula Cl nae-Qua N-CH(CH2)aCHO-tertiaryl l amyl CH3 CH3 12. A compound of the formula 13. A compound of the formula HaC-QN N-(OHz) FOG-tertiary- L/ amyl 14. A compound of the formula 15. A compound of the formula .16. A compound of the formula 17. A compound of the formula R2 halo R Q-W- -Q R 1 (H2G)m wherein R is a member selected from the group consisting of hydrogen, halogen, nitro, diloweralkylamino, lower alkyl and lower alkoxy; R is a member selected from the group consisting of halogen and lower alkyl; R is a member selected from the group consisting of hydrogen and methyl; n is a whole number from 1 to 12 inclusive; and m is a whole number from 1 to 2 inclusive.

References Cited by the Examiner UNITED STATES PATENTS 2,229,024 1/ 1941 Bruson 260-268 2,415,786 2/1947 Buck 260268 2,575,122 11/1951 Pollard et a1 260-268 2,695,295 =11/1954 Swain 260268 2,891,063 6/1959 Sommors 260--268 OTHER REFERENCES Burger: Medicinal Chemistry, pages 77-78, 2nd edition (1960).

Swain et al.: Journal American Chemical Society, vol. 76, pp. 5091-5093 (1954).

HENRY R. JILES, Acting Primary Examiner.

WALTER A. MODANCE, Examiner.

JAMES W. ADAMS, N. H. STEPNO,

Assistant Examiners. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 